Inflammation that accompanies chronic disease, if uncontrolled, leads to severe tissue damage resulting in debilitation and even death. It is well established that CD4+Foxp3+ T regulatory cells (Treg) play an essential role in the suppression of autoimmune and inflammatory responses. In addition to Treg, B cells have also emerged as an important attenuator of inflammation in a variety of diseases, including autoimmunity and hypersensitivities. We were the first to show that B cells attenuate disease severity in autoimmunity using the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Shortly thereafter the concept of regulatory B cells or Breg emerged. Even though B cells have been shown to regulate inflammation via IL-10 production, they cannot be identified by a definitive cell surface phenotype. In contrast, in our studies investigating IL-10-independent Breg mechanisms, we have successfully identified a cell surface phenotype that we have used to track and purify Breg. Of significance to the translation of our findings is that human Breg promote Treg proliferation. This is the first example of a definitive cell surface phenotype that can be used to identify and purify a specific population of Breg in both mouse and humans. To emphasize their unique function, we termed them B Treg helper cells (BTrh). The goal of this application is to gain a better understanding of the development and function of BTrh and will test the hypothesis that BTrh via their induction of Treg proliferation will have clinical relevance in the attenuation of inflammatory diseases. This hypothesis will be tested in two specific aims: Aim 1. Gain a better understanding of unique BTrh characteristics by studying their developmental status, functional requirements and localization with Treg and Aim 2. Determine the therapeutic potential of GITRL+ BTrh and to test the hypothesis that efficacy of B cell depletion by rituximab in MS is due to its inability to deplete BTrh. Together, the proposed studies represent a tightly focused coordinated series of investigations aimed at broadening the importance of BTrh in a number of clinically important inflammatory disorders in humans.